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WO1998038162A1 - Inhibiteurs de l'isoprenyle transferase - Google Patents

Inhibiteurs de l'isoprenyle transferase Download PDF

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Publication number
WO1998038162A1
WO1998038162A1 PCT/US1998/004047 US9804047W WO9838162A1 WO 1998038162 A1 WO1998038162 A1 WO 1998038162A1 US 9804047 W US9804047 W US 9804047W WO 9838162 A1 WO9838162 A1 WO 9838162A1
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Prior art keywords
alkyl
hydrogen
compound
aryl
oxygen
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PCT/US1998/004047
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English (en)
Inventor
Michael D. Lewis
Ana Maria Garcia
James J. Kowalczyk
Hu Yang
Eric Schwartz
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Eisai Co., Ltd.
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Application filed by Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Priority to AU66783/98A priority Critical patent/AU6678398A/en
Priority to US09/269,915 priority patent/US6265603B1/en
Publication of WO1998038162A1 publication Critical patent/WO1998038162A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • This invention concerns peptidomimetic isoprenyl transferase inhibitor compounds useful in the treatment of human cancers.
  • Ras oncogenes are prevalent in over 20% of all human cancers.
  • the compounds of the invention inhibit the posttranslational processing of ras proteins, thereby inhibiting ras protein function.
  • Ras proteins are present in all cell types, and are thought to take part in normal cellular signal transduction mechanisms. Ras mutations are thought to cause hyperproliferation of cells; mutated ras genes are known as oncogenes. In particular, ras oncogenes are found in approximately 30% of all lung cancer, 30% of all myeloid leukemia, 50% of all colorectal carcinoma, and 90% of all pancreatic carcinoma. Barbacid, M., Ann. Rev. Biochem., 56:779 (1987), Bos, J.L., Cancer Res. 49:4682 (1989). Examples of ras mutations include H-ras, K- ras, and N-ras.
  • the post-translational processing of ras proteins is signaled by a short carboxyl-terminus consensus sequence, known as the CAAX box.
  • This sequence signals which of two isoprenyl groups, farnesyl or geranylgeranyl, is to be attached to ras proteins by cellular enzymes.
  • a farnesyl group is a 15 carbon isoprenyl group, while a geranylgeranyl group is a 20 carbon isoprenyl group.
  • Isoprenyl group ' s are multimers of isoprene, a 5 carbon compound.
  • C is cysteine
  • A is an aliphatic amino acid
  • X the carboxyl-terminal amino acid
  • Geranylgeranylated proteins such as Rap, Rho and other small GTP-binding proteins, have similar CAAX sequences in which X is usually leucine, or occasionally is phenylalanine. In vivo, ras proteins are preferentially farnesylated.
  • Post-translational processing of the ras-encoded protein includes at least three steps.
  • reaction with farnesyl pyrophosphate attaches a farnesyl group to the Cys residue on the sulfhydryl side chain.
  • a specific protease cleaves the three carboxy-terminal amino acids.
  • Third, the carboxylic acid moiety of the now-terminal cysteine is methylated to a methyl ester.
  • the farnesyl transferase enzyme (FTase) mediates the attachment of the farnesyl group to a protein.
  • the geranylgeranyl transferase I enzyme (GGTase I) mediates the attachment of the geranylgeranyl group to a protein.
  • Post-translational processing, particularly farnesylation, of ras proteins is critical for in vivo ras protein function.
  • farnesylation of ras oncogene products is known to be essential for ras-induced cellular transformation.
  • Upstream of FTase farnesylation of a ras protein can be inhibited by mevalonate synthesis inhibitors such as lovastatin or compactin, which are HMG-CoA reductase inhibitors. Direct inhibition of FTase by short peptides or peptide-like substrates has also been demonstrated.
  • ras proteins mediate the transformation of normal cells to cancer cells in many human cancers
  • compounds which inhibit prenylation will, therefore, inhibit the growth of ras- related cancers.
  • Summary of the Invention This invention is directed to novel peptidomimetic isoprenyl transferase inhibitor compound useful in the treatment of ras-associated human cancers.
  • Ras-associated "human cancers are those in which a mutated form of the ras gene product are commonly found, e.g., lung cancers, myeloid leukemia, colorectal carcinoma, pancreatic carcinoma, and the like.
  • the invention concerns the compounds themselves, the preparation of these compounds, and the in vitro and in vivo isoprenyl transferase activity of these compounds. Another aspect of the invention is directed to the clinical use of the compounds to decrease isoprenyl transferase activity in biological systems, and to the physiological consequences of inhibition of isoprenyl transferase.
  • the compounds of the invention possess advantages for pharmaceutical use such as enhanced pharmacological selectivity and efficacy.
  • the compounds of the invention may be used clinically to treat medical conditions where a decrease in isoprenyl transferase activity is beneficial.
  • the compounds of the invention can be used to inhibit post-translational modification of oncogenic ras proteins by FTase, thereby down-regulating ras protein- stimulated cell proliferation. Accordingly, the invention is directed to the treatment of various forms of ras-associated cancer. Some compounds of the invention inhibit post-translational modification of ras proteins by the related GGTase I, which also results in down-regulation of ras protein function.
  • Certain compounds of the invention are selective or specific for FTase and are preferred over compounds which are selective for GGTase I. Further, compounds of the present invention may contain asymmetric carbon atoms and hence can exist as stereoisomers, both enantiomers and diastereomers. All stereoisomers and mixtures thereof are considered to fall within the scope of the present invention.
  • the synthetic examples cited herein provide the most preferred isomer.
  • the invention is also directed to prodrugs and pharmaceutically acceptable salts of the compounds described, and to pharmaceutical compositions suitable for different routes of drug administration and which comprise a therapeutically effective amount of a described compound admixed with a pharmacologically acceptable carrier.
  • aryl refers to aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
  • Heterocyclic aryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, and the like, all of which may be optionally substituted.
  • Carbocyclic aryl groups are groups wherein the ring atoms of the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and optionally substituted naphthyl groups.
  • optionally substituted means the substitution on aryl groups, whether carbocyclic, heterocyclic, or biaryl, with one to four substituents, the substituents being independently selected from lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, carboxy, carboxyalkyl, cyano, nitro, trihalomethyl, amino, lower alkylamino, lower acylamino or lower alkoxycarbonyl.
  • aralkyl refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like. The aryl group of an aralkyl moiety may be optionally substituted.
  • Aralkyl groups may be described herein as (C x _ y arylXC g .k alkyl) where "x-y” denotes the range of the number of carbon atoms in the aryl moiety of the aralkyl group and "a-b” denotes the range of the number of carbon atoms in the alkyl moiety of the aralkyl group.
  • organic radicals or compounds when used herein in connection with organic radicals or compounds respectively, defines them as comprising up to and including 10, preferably up to and including 6 and preferably one or two carbon atoms.
  • organic radicals or compounds may have straight chain or branched chain structures.
  • alkylamino (b) “arylamino”, and (c) “aralkylamino”, respectively, refer to the groups -NR 1 R 2 where each of RT and R 2 is independently hydrogen, alkyl, or aryl.
  • carboxamide or “carboxamido” refers to -CONR2 where each R is independently hydrogen or aryl, alkyl.
  • alkyl refers to saturated aliphatic groups including straight- chain, branched chain and cyclic groups.
  • alkenyl refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight-chain, branched-chain and cyclic groups.
  • alkynyl refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight-chain, branched-chain and cyclic groups.
  • prodrug refers to any compound that may have less intrinsic activity than the "drug” but when administered to a biological system generates the "drug” substance either as a result of spontaneous chemical reaction or by enzyme catalyzed or metabolic reaction.
  • prodrugs such as acyl esters, carbonates, and urethanes, included herein.
  • the groups illustrated are exemplary, not exhaustive and one skilled in the art could prepare other known varieties of prodrugs.
  • Such prodrugs of the compounds of Formula 1 fall within the scope of the present invention.
  • pharmaceutically acceptable salt includes salts of compounds of Formula 1 derived from the combination of a compound of this invention and an organic or inorganic acid.
  • the compounds of Formula 1 are useful in both free base and salt form. In practice the use of salt form amounts to use of base form; both forms are within the scope of the present invention.
  • treatment includes prophylactic or therapeutic administration of compounds of the invention, for the cure or amelioration of disease or symptoms associated with disease, and includes any benefits obtained or derived from the administration of the described compounds.
  • compounds of the present invention may contain asymmetric carbon atoms and hence can exist as stereoisomers, both enantiomers and diastereomers. All stereoisomers and mixtures thereof are considered to fall within the scope of the present invention.
  • the synthetic examples cited herein provide the most preferred isomer.
  • FIGURES Figure 1 shows inhibition of tumor growth in mice treated with vehicle or with compound 1.
  • the present invention relates to the use of substituted peptidomimetics which comprise compounds of the general Formula 1 and their use,
  • R1 is hydroxy, hydrogen, C- ⁇ galkyl or are independently hydrogen, C ⁇ _g alkyl, C ⁇
  • R 1 is hydrogen, lower alkyl or lower aryl
  • R 2 is hydrogen, C- ⁇ g alkyl, (Cg_4Q aryl)(C ⁇ _6 alkyl), or (C ⁇ .-i ⁇ heteroaryl)
  • R 3 is hydrogen, C- ⁇ g alkyl, (Cg_2o aryl)(C ⁇ _g alkyl);
  • R 4 is hydroxy, C ⁇
  • R5 is the residue of a natural amino acid or is D-E-F where D is C-
  • R ⁇ is hydrogen, C- ⁇ g alkyl, C- j .g acyl or when taken together with R ⁇ forms a heterocyclic ring containing from 3 to 10 carbon atoms;
  • W is C ⁇ _g alkyl, or C ⁇ .g alkenyl
  • X is oxygen, sulfur or two hydrogen atoms
  • Y is -M-O-P- where M is Cg_g alkyl, O is oxygen-Cg_4 alkyl and P is C _2Q aryl, optionally additionally mono- or polysubstituted with C _2Q aryl, C _2Q heteroaryl, C ⁇ g alkyl, C2_ ⁇ g alkenyl, C2_ ⁇ s alkynyl, C-
  • R1 is NR 7 R8 wherein R 7 and R 8 are independently hydrogen or C ⁇ _g alkyl; R 1 is hydrogen or C-
  • R 2 is hydrogen or C- j .g alkyl
  • R is hydrogen or C- ⁇ g alkyl
  • R 4 is hydroxy or C- ⁇ g alkoxy
  • R 5 is D-E-F where D is C-
  • R 6 is hydrogen, C- ⁇ g alkyl, C- j .g acyl or when taken together with R1 forms a heterocyclic ring containing from 3 to 10 carbon atoms;
  • W is CQ_8 alkyl, or C2-.8 alkenyl;
  • X is oxygen or two hydrogen atoms
  • Y is -M-O-P- where M is Cg.g alkyl, O is oxygen-C ⁇ _4 alkyl and P is Cg_2o aryl, optionally additionally mono- or polysubstituted with Cg_2o aryl, Cg_2Q heteroaryl, C ⁇ _-
  • R 7 and R 8 are independently hydrogen or C1-8 alkyl;
  • R 1 is hydrogen or C- j _3 alkyl;
  • R 2 is hydrogen or C ⁇ .g alkyl;
  • R ⁇ is hydrogen or C-
  • R 4 is hydroxy or C- ⁇ g alkoxy;
  • R ⁇ is D-E-F where D is C-
  • R 6 is hydrogen " , C ⁇
  • W is C 0 _8 alkyl;
  • X is oxygen or two hydrogen atoms;
  • Y is -M-O-P- where M is Cg.g alkyl, O is oxygen-C ⁇ _4 alkyl and P is Cg_2o aryl, optionally additionally mono- or polysubstituted with Cg_2o aryl, Cg_2 Q heteroaryl, C-
  • R is NR 7 R 8 wherein R 7 and R 8 are hydrogen
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen or C 1.4 alkyl
  • R ⁇ is hydrogen or C-
  • R 4 is hydroxy or C ⁇ .g alkoxy
  • R 5 is D-E-F where D is C- ⁇ g alkyl, E is sulfur and F is hydrogen or C ⁇ . alkyl;
  • R ⁇ is hydrogen
  • W is CQ_3 alkyl
  • X is oxygen or two hydrogen atoms
  • Y is -M-O-P- where M is C ⁇ _g alkyl, O is oxygen-C ⁇ _4 alkyl and P is Cg_2 ⁇ aryl, optionally additionally mono- or polysubstituted with Cg_2o aryl, C .20 heteroaryl, C- ⁇ ig alkyl, C2_18 alkenyl, C2_-
  • R ⁇ is the moiety wherein R 1 , R , R 2 , R 3 , R 4 , R 5 , W, X and Y are selected such that the compounds are disulfide bond-linked dimers.
  • R 4 is hydroxy or C ⁇
  • Another aspect of this invention is directed to processes for preparing compounds of Formula I. Disclosed herein are general synthetic routes for preparing the compounds of this invention. A representative synthesis of a compound of this invention, compound 1 , is shown below.
  • the "right side” may be synthesized by the route shown below:
  • the 3-thio-2-hydroxypropanoic acid starting material may be prepared by the methods described in U. S. Patent No. 2,828,208.
  • ester is desired, the following synthetic pathway may be followed.
  • Dimer compounds of the present invention may be prepared as follows.
  • the activated disulfide, compound N is treated with a solution of the appropriate thiol, in this case compound 1.
  • the mixture was stirred for 14 hours at room temperature and then chromatrographed to give the desired disulfide dimer.
  • Other dimers may be prepared in a similar manner.
  • Compounds of the present invention are administered to subjects in need of treatment in dosages which are effective to produce inhibition of isoprenyl transferases.
  • Compound 1 the most potent compound of the series, can be administered, for example, by iv infusion of a solution or suspension with a concentration of between about 1 and 10 mg/mL.
  • the total dose per subject per day should be between about 10 and 200 mg/m 2 , preferably between about 25 and 150 mg/m 2 , and more preferably between about 50 and 100 mg/m 2 of body surface area.
  • a representative dosage regimen is daily administration for 5 days followed by 2 days rest. The administration cycle may be repeated every two weeks. Those of ordinary skill in the art will recognize that modification of dosage and administration routes can be made based on subject responsiveness to treatment.
  • An alternative method of administration is by way of infusion pump, at about the concentration indicated above.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters. Preferred for certain indications are methods of administration which allow rapid access to the tissue or organ being treated, such as intravenous injections for the treatment of cancer.
  • Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxyp ropy I methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadeaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservative such as ethyl of n-propyl p-hydroxybenzoate.
  • the pharmaceutical compositions of the invention are preferably in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a " sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, such as a solution in 1 ,3-butanediol or prepared as a lyophilized powder.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders of the kind previously described.
  • drying and chromatography is performed as follows: upon completion of the reaction by TLC (or other suitable methods of analysis) the final solution is extracted with brine, dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel using hexanes/ethyl acetate as the eluent. All reactions requiring anhydrous conditions were run under dry nitrogen or argon. All compounds gave proton and carbon NMR spectra consistent with their structure.
  • Compound E A 0.5 M toluene solution (7.0 mL, 3.5 mmol) of potassium bis(trimethylsilyl)amide was added dropwise to a THF (20 mL) suspension of [2- (trimethylsilyl)ethoxymethyl]triphenylphosphonium chloride cooled at 0 °C. The mixture turned orange-red. The mixture was stirred for 30 min. during which period the reaction was allowed to warm to the room temperature. Then the mixture was cooled to 0 °C and a THF (30 mL) solution of Compound D, prepared by the method of Lewis, et al., in U. S. application 07/935,050, (520 mg, 2.12 mmol) was added.
  • a hydrolysis step is inserted into the synthetic pathway as follows: Lithium hydroxide solution, 1 M, (0.350 mL, 0.35 mmol) was added to a dioxane (0.350 mL) solution of the appropriate ester (0.035 mmol). The mixture was stirred at room temperature for 1 h. A solution of 1 N hydrochloric acid was added to quench the reaction. The mixture was extracted by ethyl acetate. The ethyl acetate solution was extracted by brine and dried over sodium sulfate. Evaporation of the acetate yielded a colorless oil (20 mg, 100%).
  • N-lodosuccinimide (19.317 g, 85.856 mmol) was added to a solution of 4-isopropylbenzaldehyde (9.77 g, 65.920 mmol) in CH2CI2 (40 mL), and the suspension was cooled to 0 °C.
  • T fluoromethanesulfonic acid (30 mL) was added via addition funnel dropwise over 10 minutes. After 2 hours, the reaction mixture was poured onto ice (200 mL), and the resulting mixture was diluted with CH2CI2 (100 mL). The organic phase was separated, and the aqueous phase was extracted with CH2CI2 (2 x 50 mL).
  • Triphenylphosphine (139 mg, 0.532 mmol) was added to a solution of compound R (59 mg, 0.266 mmol), carbon tetrabromide (177 mg, 0.532 mmol) in dichloromethane (3 mL). The solution was stirred at room temperature for 14 hours. The mixture was diluted with ethyl acetate and washed with water. Drying and chromatography yielded a colorless oil (29 mg, 39%), Compound S.
  • Compound 35 was prepared from compound V using procedures similar to those described for compound 36 from compound M.
  • Compounds 27 and 30 Compounds 27 and 30 were prepared from compound V in procedures similar to those used to prepare compounds 1 and 11 from compound M.
  • Ras proteins mediate the transformation of normal cells to cancer cells in many human cancers. Before becoming membrane associated and fully functional, ras proteins require post-translational addition of a 15 to 20 carbon prenyl group. Compounds which inhibit prenylation will, therefore, inhibit the growth of ras-related cancers.
  • each potential inhibitor compound was shown to inhibit FTase- mediated prenylation (Table 1).
  • each compound was shown to inhibit GGTase l-mediated prenylation (Table 1).
  • each compound was shown to inhibit ras protein post-translational processing in whole cells (Table 2).
  • the compounds of the invention inhibit the prenylating activity of FTase, GGTase I, or in most cases, both enzymes, with different potencies.
  • the ability of the compounds of the invention to inhibit protein processing has been demonstrated in two separate in vitro assays.
  • the ability of the disclosed inhibitor compounds to inhibit FTase was measured according to a published prenylation assay (Moores et al., J. Biol. Chem. 266:14603 (1991)). Recombinant FTase with 3 ⁇ M recombinant H-ras and 440 nM [ ⁇ H] farnesylpyrophosphate were used were used. The inhibitors were diluted in assay buffer, and each assay mixture was incubated 15 min. at 37 °C.
  • GGTase I where inhibition of GGTase I was measured, GGTase I with 5 ⁇ M recombinant, H-ras (61 L, CAIL) and 1 mM [ ⁇ H] geranylgeranyl diphosphate were used.
  • the IC50 concentration of compound needed to cause 50% inhibition of isoprenylation
  • Nanomolar concentrations of the indicated compounds were sufficient to inhibit farnesylation of ras proteins in vitro.
  • the FTase assay is preferred.
  • One embodiment of the invention selectively inhibits FTase. Substitutions which confer GGTase I specificity as taught herein also produced potent inhibitors of GGTase I.
  • each compound of the invention assayed was shown to inhibit FTase-mediated prenylation (Table 1).
  • Each compound was also shown to inhibit GGTase-mediated prenylation (Table 1).
  • H-ras (61 L) transformed NIH3T3 fibroblasts were generously provided by C. Der, Univ. N. Carolina. These fibroblasts were treated for 24 h with 50 ⁇ M lovastatin or vehicle control or the indicated concentrations of inhibitor.
  • Lovastatin is an HMG-CoA reductase inhibitor.
  • HMG-CoA reductase is an essential enzyme in the cellular synthesis of the prenyl groups with which ras proteins are modified.
  • the cells were lysed in 1% NP-40, 5 mM Tris-HCI (pH 8.0), 5 mM EDTA, 0.1 mM ⁇ /-tosyl-L-phenylalanine chloromethyl ketone, 0.1 mM ⁇ /-tosyl-L-lysine chloromethyl ketone, and 1 mM phenylmethylsulfonyl fluoride.
  • the lysate was centrifuged (15000 x g, 5 min.) and the supernatant was used as a cell extract. Total protein was separated by SDS-PAGE in 15% acrylamide gel.
  • Processed ras can be differentiated from non-processed ras by its mobility in polyacrylamide gels. After transfer to IMMOBILON PTM membrane (Millipore), the blots were probed with LA069 mouse monoclonal antibody to H-ras (Quality Biotech). All Western blots were developed using ECL chemiluminescent reagents (Amersham) and the relative amounts of farnesylated and non- famesylated ras were quantitated using the inhibition obtained by 50 ⁇ M lovastatin as 100% reference.
  • IC50 values for inhibition H-ras prenylation are presented in Table 2. Sub-micromolar concentrations are sufficient to inhibit farnesylation of ras proteins in whole cells.
  • Sub-micromolar concentrations are sufficient to inhibit farnesylation of ras proteins in whole cells.
  • the compounds of the invention inhibit the prenylating activity of FTase, GGTase, or in most cases, both enzymes.
  • the compounds inhibit these enzymes with different potencies; preferred compounds of the invention inhibit FTase more potently than GGTase.
  • EXAMPLE 4 Inhibition of human tumor xenoqraft in mice H-ras (61 L) transformed NIH3T3 fibroblasts were grown in- Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated calf serum. 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, and 0.75 mg/mL G418 (GIBCO) and incubated at 37 °C in 5% CO2.
  • GIBCO 0.75 mg/mL G418
  • HBSS Hank's balanced salt solution
  • mice Five week old female athymic nude mice were obtained from SLC (3371-8, Kotoummachi, Hamamatsu-shi, Shizuoka 431-11 , Japan) and maintained under pathogen-free conditions. The mice were subcutaneously injected in the lateral flank with 1 x 10 ⁇ H-ras transformed cells/mouse.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau composé inhibiteur de l'isoprényle transférase peptidomimétique utilisé dans le traitement des cancers humains associés à la Ras. Les cancers humains associés à la Ras sont ceux dans lesquels on trouve communément une forme mutante du produit génique de la Ras, par exemple, les cancers du poumon, la leucémie myéloïde, le carcinome colorectal, le carcinome pancréatique et analogues. La présente invention concerne lesdits composés, la préparation de ces composés et l'activité isoprényle transférase, in vivo et in vitro, de ces composés. La présente invention concerne également l'utilisation clinique de ces composés de façon à réduire une activité isoprényle transférase dans des systèmes biologiques et les conséquences physiologiques d'inhibition de l'isoprényle transférase.
PCT/US1998/004047 1997-02-27 1998-02-27 Inhibiteurs de l'isoprenyle transferase WO1998038162A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU66783/98A AU6678398A (en) 1997-02-27 1998-02-27 Inhibitors of isoprenyl transferase
US09/269,915 US6265603B1 (en) 1997-02-27 1998-02-27 Inhibitors of isoprenyl transferase

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4049597P 1997-02-27 1997-02-27
US60/040,495 1997-02-27

Publications (1)

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WO1998038162A1 true WO1998038162A1 (fr) 1998-09-03

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US (1) US6265603B1 (fr)
AU (1) AU6678398A (fr)
WO (1) WO1998038162A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204293B1 (en) 1995-11-06 2001-03-20 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6221865B1 (en) 1995-11-06 2001-04-24 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6310095B1 (en) 1995-11-06 2001-10-30 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6486202B1 (en) 2001-04-13 2002-11-26 Eisai Company, Limited Inhibitors of isoprenyl transferase
IL163711A0 (en) * 2002-03-08 2005-12-18 Eisai Co Ltd Macrocyclic compounds useful as pharmaceuticals
US7915306B2 (en) * 2002-03-08 2011-03-29 Eisai Co., Ltd. Macrocyclic compounds useful as pharmaceuticals
CN101778627B (zh) * 2007-07-25 2016-04-13 卫材R&D管理株式会社 用于治疗癌症的多激酶抑制剂

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025086A1 (fr) * 1994-03-15 1995-09-21 Eisai Co., Ltd. Inhibiteurs d'isoprenyle-transferase
WO1995034535A1 (fr) * 1994-06-10 1995-12-21 Rhone-Poulenc Rorer S.A. Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent
US5602098A (en) * 1993-05-18 1997-02-11 University Of Pittsburgh Inhibition of farnesyltransferase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5602098A (en) * 1993-05-18 1997-02-11 University Of Pittsburgh Inhibition of farnesyltransferase
WO1995025086A1 (fr) * 1994-03-15 1995-09-21 Eisai Co., Ltd. Inhibiteurs d'isoprenyle-transferase
WO1995034535A1 (fr) * 1994-06-10 1995-12-21 Rhone-Poulenc Rorer S.A. Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204293B1 (en) 1995-11-06 2001-03-20 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6221865B1 (en) 1995-11-06 2001-04-24 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6310095B1 (en) 1995-11-06 2001-10-30 University Of Pittsburgh Inhibitors of protein isoprenyl transferases
US6693123B2 (en) 1995-11-06 2004-02-17 University Of Pittsburgh Inhibitors of protein isoprenyl transferases

Also Published As

Publication number Publication date
US6265603B1 (en) 2001-07-24
AU6678398A (en) 1998-09-18

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